A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML

Article metrics

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2

Accession codes

Accessions

Gene Expression Omnibus

References

  1. 1

    The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

  2. 2

    Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016; 374: 2209–2221.

  3. 3

    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462: 739–744.

  4. 4

    Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17: 225–234.

  5. 5

    Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18: 553–567.

  6. 6

    Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 2012; 483: 484–488.

  7. 7

    Inoue S, Li WY, Tseng A, Beerman I, Elia AJ, Bendall SC et al. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 2016; 30: 337–348.

  8. 8

    Cairns RA, Mak TW . Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov 2013; 3: 730–741.

  9. 9

    Chen C, Liu Y, Lu C, Cross JR, Morris JP, Shroff AS et al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev 2013; 27: 1974–1985.

  10. 10

    Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P et al. Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell 2014; 14: 329–341.

  11. 11

    Stein EM . IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol 2015; 28: 112–115.

  12. 12

    Birendra KC, DiNardo CD . Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk 2016; 16: 460–465.

  13. 13

    Graham SM, Vass JK, Holyoake TL, Graham GJ . Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cells 2007; 25: 3111–3120.

  14. 14

    Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR . A stem cell molecular signature. Science 2002; 298: 601–604.

  15. 15

    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

Download references

Acknowledgements

This work was funded by project and program grants (RWJ and LMK) from the National Health and Medical Research Council of Australia (NHMRC) and a grant from the Peter Mac Foundation (LMK). RWJ was supported by an NHMRC Fellowship and LMK was supported by a Victorian Cancer Agency fellowship.

Author information

Correspondence to L M Kats or R W Johnstone.

Ethics declarations

Competing interests

RN and KEY are employees of and have ownership interest (including some with patents) in Agios Pharmaceuticals. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading